tbuckley/cabot-search huggingface dataset:
Abstract IA008: Biology of metastasis-competent circulating tumor cells
Authors: Catherine Alix-Panabières
Journal: Cancer Research (2023)

Abstract The characterization of circulating tumor cells (CTCs) holds promises for precision medicine because these cells are an important clinical indicator of treatment efficacy. We established the first and still only nine permanent colon CTC lines from peripheral blood samples of a patient with metastatic colon cancer collected at different time points during treatment and cancer progression. The study objectives were (i) to compare the gene expression profiles of these CTC lines, and (ii) to determine the main features acquired during treatment. The number of upregulated genes was higher in the CTC lines obtained after treatment, indicating that they acquired properties to escape treatment pressure. Among these upregulated genes, some are involved in the mTOR and PI3K/AKT signaling pathways. Moreover, cytidine deaminase expression was significantly increased in the CTC lines obtained after failure of the first- and second-line 5-fluorouracile-based treatments, suggesting that these CTCs can eliminate this specific drug and resist to therapy. Several enzymes involved in xenobiotic metabolism also were upregulated after treatment, suggesting the activation of detoxification mechanisms in response to chemotherapy. Finally, the significant higher expression of aldolase B in four of the six CTC lines obtained after treatment withdrawal and cancer progression indicated that these clones originated from liver metastases. In conclusion, these CTC lines generated at different time points during treatment of metastatic colon cancer in a single patient are characterized by the deregulation of different genes that promote (i) drug resistance, (ii) xenobiotic and energy metabolism, and (iii) stem cell properties and plasticity. Citation Format: Catherine Alix-Panabières. Biology of metastasis-competent circulating tumor cells [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA008.
Abstract B019: Identify features of fibroblast and macrophage which regulate metastasis of triple-negative breast cancer
Authors: Woochan Lee, Hyewon Chung, Woohang Heo, Hyeong-Gon Moon, Seung Hyeok Seok, Jong-Il Kim
Journal: Cancer Research (2023)

Abstract The tumor microenvironment (TME), which the cancer is known to remodel, can interact with cancer in various ways, such as promoting or hindering metastasis. The challenge with comprehending TME is that each patient's individual variance makes it difficult to carry out a consistent analysis. We used the PDX model to analyze the alterations entirely brought about by cancer cells of each patient in the same environment exclusively. In 121 breast cancer patients, we created a PDX model and performed WES and RNA-seq. We repeatedly performed metastatic induction tests on the models of 26 TNBC patients among the PDX models we generated. The replicated experiments confirmed that cancer cells with frequent metastasis usually spread well, while cancer cells with seldom metastases rarely metastasize. For each of the five samples that had the greatest and worst rates of metastasis, the pre-metastatic xenograft tumor was analyzed using scRNA-seq. Metastasis could not be predicted by only cancer cells because there was no difference between the two groups. Still, fibroblasts and macrophages had distinct gene markers before metastasis which can predict metastasis. To explore TME that develops pre-metastatic niches (PMN) in organs that would be metastasis targets, we developed a metastatic model using 4T1 cell lines. Daily lung macrophage RNA-seq, lung WES, and lung scRNA-seq procedures were carried out for four weeks to examine the precise timing of metastasis and the daily changes in the transcriptome. Surprisingly, a few days before the presence of any cancer cells, the gene expression of lung macrophages had already undergone significant modification. Additionally, only injections of tumor-conditioned media that mimicked metastasis could activate PMN in lung macrophages. Citation Format: Woochan Lee, Hyewon Chung, Woohang Heo, Hyeong-Gon Moon, Seung Hyeok Seok, Jong-Il Kim. Identify features of fibroblast and macrophage which regulate metastasis of triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B019.
Abstract PR009: Integrative pan-cancer genomic and transcriptomic analyses of refractory metastatic cancer
Authors: Yoann Pradat, Julien Viot, Konstantin Gunbin, Andrei Iurchenko, Marc Deloger, Luigi Cerbone, Guillaume Grisay, Loic Verlingue, Veronique Scott, Stefan Michiels, Antoine Hollebecque, Gerome Jules-Clement, Antoine Laine, Luc Friboulet, Laura Mezquita, Yohann Loriot, Benjamin Besse, Fabrice Andre, Paul-Henry Cournede, Daniel Gautheret, Sergey Nikolaev
Journal: Cancer Research (2023)

Abstract Metastatic relapse after treatment is the primary cause of cancer morbidity and mortality. While genetic mechanisms of primary tumors and, to a lesser extent, metastatic cancers have been studied in large cohorts, refractory metastatic tumors are not yet sufficiently characterized. Markers of aggressiveness and resistance that molecular profiling can extract from these tumors have yet to be identified and incorporated into clinical care. In this study, we present a pan-cancer cohort of 1,031 metastatic tumors (which we refer to as META-PRISM) that are resistant to at least one systemic therapy or with no approved treatment options. We retrieved the complete clinical history of patients and performed whole-exome (n=571) and transcriptome sequencing (n=947) for this cohort. The prevalence of detected cancer biomarkers was assessed and compared to an external cohort of primary tumors. In the META-PRISM cohort, we observed an increase in (i) whole-genome duplication frequency, (ii) tumor mutational burden, (iii) germline cancer-predisposing variants, and (iv) somatic alterations in cancer genes, including KRAS, EGFR, CCND1, MYC, and TP53, as compared to the tumor type-matched primary tumors. The most extensive increase in genomic variation at metastatic stage was observed in prostate cancer. We also identified enrichment of standard-of-care resistance biomarkers in most cancer types. However, only 7.6% of tumors harbored at least one such biomarker, indicating that the current understanding of resistance mechanisms remains insufficient. Our cohort demonstrated a significantly improved 6-month survival prediction from models incorporating molecular markers over models with only clinical markers for breast cancer patients and to a lesser extent for other studied tumor types. Overall, our data establish a unique resource for investigating treatment resistance mechanisms and performing predictive analyses in cancer. Citation Format: Yoann Pradat, Julien Viot, Konstantin Gunbin, Andrei Iurchenko, Marc Deloger, Luigi Cerbone, Guillaume Grisay, Loic Verlingue, Veronique Scott, Stefan Michiels, Antoine Hollebecque, Gerome Jules-Clement, Antoine Laine, Luc Friboulet, Laura Mezquita, Yohann Loriot, Benjamin Besse, Fabrice Andre, Paul-Henry Cournede, Daniel Gautheret, Sergey Nikolaev. Integrative pan-cancer genomic and transcriptomic analyses of refractory metastatic cancer [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR009.
Abstract B021: Piezo1 and ROCK2 promote fast amoeboid migration in confined environments
Authors: Alexa Caruso, Neelakshi Kar, Jeremy Logue
Journal: Cancer Research (2023)

Abstract Cell migration through confined environments may induce a phenotypic transition to fast amoeboid (leader bleb-based) migration. However, the molecular mechanism(s) controlling this phenotypic transition remain poorly understood. Here, we show that regulation of intracellular calcium levels by the plasma membrane tension sensor, Piezo1, promotes the Leader Bleb-Based Migration (LBBM) of melanoma cells. Using a ratiometric assay, intracellular calcium is shown to rise with increasing levels of confinement. Chelation of extracellular and intracellular calcium by BAPTA and BAPTA-AM, respectively, inhibits LBBM. Moreover, in highly motile cells, we found intracellular calcium levels to be dramatically increased at the cell rear. Using the Piezo1 inhibitor, GsMTx4, and RNAi, we can inhibit the phenotypic transition to fast amoeboid (leader bleb-based) migration. Therefore, we wondered if Piezo1 through calcium/calmodulin activates Myosin Light Chain Kinase (MLCK) to promote actomyosin contractility and amoeboid migration. Using a microchannel based assay, we find that ROCK2 and not MLCK, promotes amoeboid migration. Altogether, our work reveals an unanticipated collaboration between Piezo1 and ROCK2 in amoeboid migrating melanoma cells. Citation Format: Alexa Caruso, Neelakshi Kar, Jeremy Logue. Piezo1 and ROCK2 promote fast amoeboid migration in confined environments [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B021.
Abstract IA025: About motifs, non-codingRNAs and metastases
Authors: George A. Calin
Journal: Cancer Research (2023)

Abstract MicroRNA and other short or long non-codingRNAs alterations are involved in the initiation, progression and metastases of human cancer. The main molecular alterations are represented by variations in gene expression, usually mild and with consequences for a vast number of target protein coding genes. The causes of the widespread differential expression of non-codingRNAs in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the processing machinery. MicroRNA and other short or long non-codingRNAs expression profiling of human tumors has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify non-codingRNAs that may represent downstream targets of activated oncogenic pathways or that are targeting protein coding genes involved in cancer. Recent studies proved that miRNAs and non-coding ultraconserved genes are main candidates for the elusive class of cancer predisposing genes and that other types of non-codingRNAs participate in the genetic puzzle giving rise to the malignant phenotype. These discoveries could be exploited for the development of useful markers for diagnosis and prognosis, as well as for the development of new RNA-based cancer therapies. Citation Format: George A. Calin. About motifs, non-codingRNAs and metastases [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA025.
Abstract A010: MYC as a master regulator of dormancy in triple negative breast cancer
Authors: Charlotte Roelofs, Kellie A. Mouchemore, Anannya Chakrabarti, Richard P. Redvers, Robin L. Anderson
Journal: Cancer Research (2023)

Abstract Dormancy is a major clinical problem in breast cancer. Although the five-year survival rate is high, 15% of the patients will relapse. Cancer cells that disseminate from the tumor (DTCs) can enter a dormant state that allows survival in the face of standard-of-care therapies. These DTCs are the source of cancer recurrence. Currently little is known about the molecular drivers that initiate dormancy. MYC is a well-known oncogene that is aberrantly regulated in many cancers, including breast cancer. It is involved in proliferation, tumorigenesis, and diapause. We propose that MYC is also a master regulator of dormancy. To investigate its role in dormancy, we generated cell lines with regulatable levels of MYC expression. Using an in vitro dormancy assay, we have shown that reduced MYC levels induce dormancy in otherwise aggressive cell lines. In mice bearing human breast tumors, the loss of MYC activity following primary tumor removal greatly reduces the extent of metastasis. The DTCs in lungs, livers, spine, and femurs are maintained as small clusters with few cells, while control mice have many and large metastases. MYC reduction maintains the DTCs in this dormant-like state for at least 32 days after primary tumor removal. Importantly, when MYC levels are restored, the DTCs exit the dormant state, and overt metastasis ensues. Currently, we are comparing the transcriptomes of dormant DTCs to actively growing metastatic cells to generate a MYC-driven dormancy signature that will elucidate potential dormancy genes to target therapeutically in the clinic. To complement our genetic studies, we are investigating pharmacological suppression of MYC activity. The bromodomain inhibitor I-BET151 reduces MYC protein levels and induces dormancy in our in vitro assay. Mice treated with I-BET151 after primary tumor removal had significantly reduced levels of metastasis in lung, liver, and spine when compared to their non-treated counterparts. Testing of this compound in an immune-competent preclinical model is currently underway. Our data imply that MYC is an important regulator of dormancy in breast cancer. Our future experiments will elucidate dormancy genes as potential targets that could lead to life-saving therapies in the clinic. Citation Format: Charlotte Roelofs, Kellie A. Mouchemore, Anannya Chakrabarti, Richard P. Redvers, Robin L. Anderson. MYC as a master regulator of dormancy in triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A010.
Abstract PR001: Codon-bias and tRNA modifications as drivers of melanoma metastasis
Authors: Elena Piskounova
Journal: Cancer Research (2023)

Abstract Only tumor cells that are able to enhance their stress response pathways, are able to successfully metastasize and colonize distant organs. In yeast, reprogramming of translation through modification of the tRNA anticodon loop in response to stress has been shown to be a central adaptive mechanism of survival. Distinct tRNA modifications increase translational efficiency of certain codons. These modifications are upregulated and are essential for survival under a range of stressors, including oxidative stress. The adaptive proteome is therefore encoded by specific transcripts with a distinct codon bias and regulated by these tRNA modifications. We have identified several stress-induced tRNA anticodon loop modifications in metastasizing melanoma cells that drive codon-biased translation of the adaptive pro-metastatic proteome. One of these modifications specifically regulates stress-induced translation of selenocysteine-containing proteins. Selenoproteins are central to stress resistance including oxidative and proteotoxic stress. We have identified and characterized the methyltransferase that regulates this modification and enables translation of the metastatic selenoproteome. More broadly, by combining biochemical approaches with in vivo models of melanoma metastasis, we have now identified several other enzymes responsible for multiple tRNA anticodon modifications as novel and targetable drivers of metastatic disease. Our work aims to establish how tRNA anticodon modifications and a distinct codon bias reprogram the metastatic proteome as a therapeutically targetable stress response mechanism. Citation Format: Elena Piskounova. Codon-bias and tRNA modifications as drivers of melanoma metastasis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR001.
Abstract IA001: Metastasis initiating cells and ecosystems
Authors: Joan Massagué
Journal: Cancer Research (2023)

Abstract Metastasis is initiated and sustained through therapy by cancer cells with stem-like properties, termed metastasis initiating cells (MICs). Recent work suggests that MICs are malignant cells that adopted a regenerative stem-cell phenotype with intrinsic programs to survive the physical, immune and metabolic stresses of the metastatic process, enter a slow-cycling state for dormancy, and establish supportive interactions with organ-specific ecosystems for eventual outgrowth and recurrence. Notably, relapse frequently develops from disseminated MICs that remain dormant in distant organs after the apparently successful treatment of a primary tumor. During dormancy, MICs fluctuate between immune evasive quiescent and cell cycle reentry states, which exposes them to elimination by the immune system. By combining novel immunocompetent mouse models of lung adenocarcinoma indolent metastasis, in vivo genetic screens, immune profiling, and pre-clinical anti-tumor drug testing, we identified specific pathways in reawakened MICs that drive immune-mediated clearance and can be therapeutically activated to hasten the elimination of residual disseminated disease. Moreover, analysis of brain metastasis with advanced imaging reveals that the interplay between MICs and their host ecosystem is influenced by the architecture of metastatic colonies. Thus, lung adenocarcinoma and triple-negative breast cancer metastases grow by spreading on the basement membrane of brain capillaries, forming perivascular tumor colonies that closely interact with microglia and astrocytes. In contrast, HER2+ breast cancer cells adopt a spheroidal growth pattern that is driven by tumor-derived extracellular matrix and restricts microglia and astrocyte infiltration. The use of single-cell analytics revealed distinct microglia activation states, MIC dependencies and vulnerabilities associated with these different growth patterns. This progress sheds light on the complex and dynamic interplay between MICs and their host ecosystems and point at therapeutically actionable targets to hasten the elimination of disseminated disease. Citation Format: Joan Massagué. Metastasis initiating cells and ecosystems [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA001.
Abstract A037: PROTACs as emergent treatment modality of metastatic prostate cancer. [R
Authors: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Partha Pratim Sarma, Satish Katike, Adilakshmi Gandham
Journal: Cancer Research (2023)

Abstract Prostate cancer is one of the most commonly diagnosed and fourth leading cause of cancer death in men, with low survival rates for metastatic cancers. Androgen receptor (AR) is one of the most altered Oncogenes in castration-resistant prostate cancer (mCRPC). Suppression of AR signalling is one of the common strategies to treat prostate cancer. Androgen deprivation therapy (ADT) has been the backbone therapy for decades and demonstrated survival benefit when used alongside other therapies including Docetaxel, cabazitaxel or hormone based anti-androgen therapies such as Enzalutamide, abiraterone, darolutamide, and apalutamide. Unfortunately, amplification or mutation in AR gene along with its associated pathway such as alteration of PI3K pathway or upregulation of MYC oncogene drive mCRPC cell proliferation and confers resistance to existing therapies. To overcome such resistance mechanisms, targeted therapy towards Androgen receptor has emerged, where ligand conjugated small molecule inhibitors using proteolysis targeting chimera (PROTAC) strategy, could effectively downregulate the AR expression. Several PROTACs as ‘Androgen Receptor Degraders (ARD)’ are showing promising activity in early-stage clinical studies. Although a promising strategy, challenges exist for its development in future; given that finding the most appropriate protein-protein interaction is essential to find optimal ligand to successfully design PROTAC. Similarly, challenges to optimize safety and efficacy of PROTACs in the clinic, also remain to be addressed. Here we aim to provide comprehensive review, including patent landscape of the therapeutic benefits of using PROTACs and its future development prospect in context to metastatic prostate cancer. Citation Format: Prashant Kashinath Bhavar, Uday Kumar Surampudi, Partha Pratim Sarma, Satish Katike, Adilakshmi Gandham. PROTACs as emergent treatment modality of metastatic prostate cancer. [R [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A037.
Abstract B038: Remodeling the extracellular matrix environment and establishing distinct immune cell profiles enables the formation of brain metastasis in non-small cell lung cancer adenocarcinoma
Authors: Albert R. Wang, Jared Brown, Andrew Baschnagel, Darya Buehler, Christina Kendziorski, Gopal Iyer
Journal: Cancer Research (2023)

Abstract Dissemination of tumor cells from the primary site of the lung to distant sites in non-small cell lung cancer (NSCLC) is poorly understood. With distinct mutation signatures in patients, altering pathways is critical to preventing tumor cell dissemination to distant sites. Towards this, we characterized 21 "trios" patient-matched brain metastases (BrM), primary tumors (LT), and normal samples (LN), revealing a pattern of extracellular matrix remodeling which suppressed immune cell infiltration. Our objectives were to (i) determine if clinically sampled primary lung tumors encode gene expression patterns distinct from normal tissue, suggestive of increased tumor invasiveness including brain metastasis, and (ii) determine the biologic underpinning of immune-suppressive information carryover from primary lung tumor to brain metastasis. Transformation of the normal lung cells to primary tumor cells suggested a breakdown in ECM axes primarily governed by upregulation of collagen (COL1A1, COL1A2, COL3A1, COL10A1), fibronectin (FN1), and matrix metalloproteinases (MMP7, MMP9, MMP11, MMP12, MMP13, MMP14) genes. Collectively, the primary tumor cells used MMPs to break down the main components of lung ECM and reorganized collagen and fibronectin in the tumor microenvironment to facilitate migration and invasion. Migration and subsequent cell adhesion in the brain microenvironment revealed upregulation of neural cell adhesion molecule (NCAM1) and phosphoprotein 1 (SPP1). These changes in ECM profiles between LT and BrM signify primary tumor cells' adaptation in the brain microenvironment. Further computational deconvolution revealed reduced HLA class II gene expression (HLA-DMA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB2, HLA-DRA) correlated with lower CIBERSORTx enrichment scores of immune cell populations in BrM. Overall, using the matched sequencing information, we will present the underlying signaling gradients that dictate dissemination of primary lung tumor cells to the brain environment in the background of altered ECM environment using cellular models harboring EGFR, KRAS, and ALK driver mutations. Citation Format: Albert R. Wang, Jared Brown, Andrew Baschnagel, Darya Buehler, Christina Kendziorski, Gopal Iyer. Remodeling the extracellular matrix environment and establishing distinct immune cell profiles enables the formation of brain metastasis in non-small cell lung cancer adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B038.